Method of treating pain by administering 24 hour oral opioid formulations exhibiting rapid rate of initial rise of plasma drug level

ABSTRACT

Patients are treated with 24-hour oral sustained release opioid formulations which, upon administrations, provide an initially rapid opioid absorption such that the minimum effective analgesic concentration of the opioid is more quickly achieved. These sustained release opioid formulations include an effective amount of at least one retardant material to cause said opioid analgesic to be released at a such a rate as to provide an analgesic effect after oral administration to a human patient for at least about 24 hours, and are characterized by providing an absorption half-life from 1 to about 8 hours. A method of titrating a human patient utilizing these sustained release opioid formulations is also disclosed.

The present invention relates to bioavailable sustained-releasepharmaceutical formulations of analgesic drugs, in particular opioidanalgesics, which provide an extended duration of effect when orallyadministered.

It is the intent of all sustained-release preparations to provide alonger period of pharmacologic response after the administration of thedrug than is ordinarily experienced after the administration of therapid release dosage forms. Such longer periods of response provide formany inherent therapeutic benefits that are not achieved withcorresponding short acting, immediate release preparations. This isespecially true in the treatment of cancer patients or other patients inneed of treatment for the alleviation of moderate to severe pain, whereblood levels of an opioid analgesic medicament must be maintained at atherapeutically effective level to provide pain relief. Unlessconventional rapid acting drug therapy is carefully administered atfrequent intervals to maintain effective steady state blood levels ofthe drug, peaks and valleys in the blood level of the active drug occurbecause of the rapid absorption, systemic excretion of the compound andthrough metabolic inactivation, thereby producing special problems inmaintenance of analgesic efficacy.

The prior art teaching of the preparation and use of compositionsproviding the sustained-release of an active compound from a carrier isbasically concerned with the release of the active substance into thephysiologic fluid of the alimentary tract. However, it is generallyrecognized that the mere presence of an active substance in thegastrointestinal fluids does not, by itself, insure bioavailability.

In order to be absorbed, the active drug substance must be in solution.The dissolution time required for a given proportion of an activesubstance from a unit dosage form is determined as the proportion of theamount of active drug substance released from a unit dosage form over aspecified time base by a test method conducted under standardizedconditions. The physiologic fluids of the gastrointestinal tract are themedia for determining dissolution time. The present state of the artrecognizes many satisfactory test procedures to measure dissolution timefor pharmaceutical compositions, and these test procedures are describedin official compendia world wide.

The primary principle guiding the use of opioid analgesics in themanagement of chronic pain is the individualization of dosages to meetthe different and changing opioid requirements among and within eachindividual patient. Pain management authorities stress the importance oftitration. Titration to the appropriate dose for a particular patient isnecessitated by the wide inter-individual differences in the response ofdifferent patients to given doses of opioids. While a multitude offactors are responsible for wide inter-individual differences in theresponse to opioid analgesics, one important factor is rooted in thewide inter-individual variation in metabolism and pharmacokcinetics.

Those opioids which are most efficiently titrated are those withrelatively short elimination half-lives in the range of 3 to 5 hours(e.g., morphine, hydromorphone, oxycodone) as compared to long (12 to 72hours) and more variable half-life analgesics(e.g., methadone,levorphanol). The shorter half life drugs approach steady-stateconcentrations in approximately a day rather than in several days to aweek or more. Only at steady-state can one expect that the balancebetween efficacy and side effects will persist at a given dosingschedule. Having confidence that the patient is at approximatesteady-state a day or so following initiation of dosing allows for muchquicker assessment of whether the dosage is appropriate for thatindividual.

Once-a-day orally administrable dosage forms have previously beendeveloped in the art and are commercially available. Presently, however,there are no commercially available sustained-release 24-hour opioidanalgesic preparations; however, experience with the 12-hour sustainedrelease preparations have led to a general understanding in the medicalcommunity that in order to titrate a patient who is to receive opioidanalgesic therapy it is necessary to use an immediate release opioidanalgesic dosage form, such as a parenteral formulation, an immediaterelease solution or tablet, or the like. Only after a suitablesteady-state level is achieved in the patient by using immediate releaseopioid preparations may a patient be switched to a sustained releaseoral opioid formulation.

It therefore follows that it would be very desirable for practitionersto have available a sustained-release opioid analgesic preparation whichprovides appropriate pharmacokinetic parameters (e.g., absorptionprofile) and accompanying pharmacodynamic response in the patient (e.g.,relief from pain) such that the same dosage form may be used to bothtitrate a patient receiving opioid analgesic therapy and used in chronicmaintenance therapy after titration of the patient. This would eliminatethe need to first titrate a patient on an immediate release opioiddosage form before switching the patient to a sustained-release dosageform for chronic therapy as described above. Preferably thesustained-release preparations will provide a duration of effect lastinglonger than about twelve hours such that a drug that may be administeredto a patient only once a day. Preferably, the sustained release dosageform will not only provide effective pain relief for a duration ofgreater than about 12 hours, but will additionally provide apharmacokinetic and pharmacodynamic profile which will allow a patientwho is to receive opioid analgesic therapy to be titrated andchronically treated with the same sustained-release dosage form.

Many of the oral opioid analgesic formulations that are currentlyavailable in the market must be administered every four to six hoursdaily; a selected few are formulated for less frequent 12 hour dosing.

There is also a need to develop a drug formulation which provides anabsorption profile which is suitable for both titrating a patient who isreceiving opioid analgesic therapy and which also provides sustainedrelease of an opioid analgesic sufficient to provide analgesia for atleast about 12 hours duration. This would eliminate the need to firsttitrate a patient with immediate release dosage forms (e.g. parenteral,oral, rectal) of opioid analgesic and then switch the patient to asustained release form of the opioid analgesic.

Morphine, which is considered to be the prototypic opioid analgesic, hasbeen formulated into twice-daily controlled-release formulations (i.e.,MS Contin® tablets, commercially available from Purdue FrederickCompany; and Kapanol®, commercially available from F. H. Faulding andCompany; and Oramorph® S R, previously referred to as Roxanol® S R,commercially available from Roxane).

An orally administrable opioid formulation which would provide anextended duration of analgesia without higher incidence of adverseeffects would be highly desirable. Such an oral sustained-releaseformulation of an opioid analgesic would be bioavailable and provideeffective steady-state blood levels (e.g., plasma levels) of the drugwhen orally administered such that a duration of analgesic efficacyabout 24 hours or more is obtained.

OBJECTS AND SUMMARY OF THE INVENTION

It is accordingly an object of the present invention to provide a methodfor treating patients in moderate to severe pain with an orallyadministered pharmaceutical dosage form of an opioid analgesic that issuitable for once-a-day administration.

It is yet another object of the present invention to provide a methodfor treating patients with a once-a-clay opioid analgesic formulationwhich provides greater analgesic efficacy than that which is obtainablewith the preferred Q12H (every 12 hour) analgesic therapies.

It is further an object of the present invention to provide an opioidanalgesic dosage form which provides sustained-release of the opioid andis also capable for use in titrating a patient receiving opioidanalgesic therapy.

In accordance with the above objects and others, the present inventionis related in part to the surprising discovery that in order to providea 24 hour dosage form of an opioid analgesic, it is critical toformulate a sustained release formulation in pain with an analgesicpreparation which provides an initially rapid opioid release so that theminimum effective analgesic concentration can be quickly approached inmany patients who have measurable if not significant pain at the time ofdosing. Due to the unique release profile of the dosage form of theinvention, it is possible to use a single dosage form according to thepresent invention to titrate a patient receiving opioid analgesictherapy while providing sustained-release of an opioid analgesic toonce-a-day sustained release oral dosage opioid formulations whichcomprise an opioid analgesic and an effective amount of at least oneretardant material to cause the opioid analgesic to be released at aneffective rate to provide an analgesic effect after oral administrationto a human patient for at least about 24 hours.

The inventive formulations, when administered in humans, provide aninitially rapid rate of rise in the plasma concentration of the opioidcharacterized by providing an absorption half-life from 1.5 to about 8hours. In preferred embodiments, the inventive once-daily oral sustainedrelease formulations provides an absorption half-life from 2 to about 4hours.

The present invention is also directed to a method for titrating humanpatients with a sustained release oral opioid formulation. The firststep of this method comprises administering to a human patient on aonce-a-day basis a unit dose of the inventive once-a-day oral sustainedrelease opioid formulations described above and in the followingparagraphs. Thereafter, the method includes the further step ofmonitoring pharmacokinetic and pharmacodynamic parameters elicited bysaid formulation in said human patient and determining whether saidpharmacokinetic and/or pharmacodynamic parameters are appropriate totreat said patient on a repeated basis. The patient is titrated byadjusting the dose of said opioid analgesic administered to the patientby administering a unit dose of said sustained release opioid analgesicformulation containing a different amount of opioid analgesic if it isdetermined that said pharmacokinetic and/or said pharmacodynamicparameters are not satisfactory or maintaining the dose of said opioidanalgesic in the unit dose at a previously administered amount if saidpharmacokinetic and/or pharmacodynamic parameters are deemedappropriate. The titration is continued by further adjusting the dose ofthe opioid analgesic until appropriate steady-statepharmacokinetic/pharmacodynamic parameters are acheived in the patient.Thereafter, the administration of the dose of the opioid analgesic inthe oral sustained release formulation is continued on a once-a-daybasis until treatment is terminated.

The term “bioavailability” is defined for purposes of the presentinvention as the extent to which the drug (e.g., opioid analgesic) isabsorbed from the unit dosage forms.

The term “sustained release” is defined for purposes of the presentinvention as the release of the drug (e.g., opioid analgesic) at such arate that blood (e.g., plasma) levels are maintained within thetherapeutic range but below toxic levels over a period of time of about24 hours or longer.

The phrase “rapid rate of rise” with regard to opioid plasmaconcentration is defined for purposes of the present invention assignifying that the formulation provides a T_(1/2) (abs), or half-lifeof absorption, from 1.5 about hours to about 8 hours.

The term T_(1/2) (abs) is defined for purposes of the present inventionas the amount of time necessary for one-half of the absorbable dose ofopioid to be transferred to plasma. This value is calculated as a “true”value (which would take into account the effect of eliminationprocesses), rather than an “apparent” absorption half-life.

The term “steady state” means that a plasma level for a given drug hasbeen achieved and which is maintained with subsequent doses of the drugat a level which is at or above the minimum effective therapeutic leveland is below the minimum toxic plasma level for a given drug. For opioidanalgesics, the minimum effective therapeutic level will be a partiallydetermined by the amount of pain relief achieved in a given patient. Itwill be well understood by those skilled in the medical art that painmeasurement is highly subjective and great individual variations mayoccur among patients.

The terms “maintenance therapy” and “chronic therapy” are defined forpurposes of the present invention as the drug therapy administered to apatient after a patient is titrated with an opioid analgesic to a steadystate as defined above.

BRIEF DESCRIPTION OF THE DRAWINGS

The following drawings are illustrative of embodiments of the inventionand are not meant to limit the scope of the invention as encompassed bythe claims.

FIG. 1 is a graphical representation of the mean sedation vs. time curvefor Example 1 (fasted);

FIG. 2 is a graphical representation of the mean sedation vs. time curvefor Example 2 (fasted);

FIG. 3 is a graphical representation of the mean respiratory rate vs.time curve for Example 1 (fasted);

FIG. 4 is a graphical representation of the mean respiratory rate vs.time curve for Example 2 (fasted);

FIG. 5 is a graphical representation of the mean pupil size v. timecurve for Example 1 (fasted);

FIG. 6 is a graphical representation of the mean pupil size vs. timecurve for Example 2 (fasted);

FIG. 7 is a graphical representation of the means subject questionnairevs. time curve for Example 1 (fasted);

FIG. 8 is a graphical representation of the means subject questionnairevs. time curve for Example 2 (fasted);

FIG. 9 is a graphical representation of the mean plasma morphineconcentration-time profile obtained with the Comparative Example (MSContin 30 mg) (fasted) as compared to the capsules of Example 1 (fed andfasted) and Example 2 (fasted);

FIG. 10 is a graphical representation of the mean plasma morphineconcentration-time profile obtained with the Comparative Example (MSContin 30 mg) (fasted) as compared to the capsules of Example 3 (fed andfasted);

FIG. 11 is a graphical representation of the mean sedation vs. timecurve for Example 3 (fasted);

FIG. 12 is a graphical representation of the mean respiratory rate vs.time curve for Example 3 (fasted);

FIG. 13 is a graphical representation of the mean pupil size v. timecurve for Example 3 (fasted); and

FIG. 14 is a graphical representation of the mean subject modifiedspecific drug effect questionnaire vs. time curve for Example 2(fasted).

DETAILED DESCRIPTION

Even at steady-state dosages of opioid analgesics, most patients remainin measurable or significant pain. The state-of-the-art approach tocontrolled release opioid therapy is to provide formulations whichexhibit zero order pharmacokinetics and have minimal peak to troughfluctuation in opioid levels with repeated dosing. This zero orderrelease provides very slow opioid absorption, and a generally flat serumconcentration curve over time. A flat serum concentration curve isgenerally considered to be advantageous because it would in effect mimica steady-state level where efficacy is provided but side effects commonto opioid analgesics are minimized. However, by formulating sustainedrelease opioids in this manner, it has been discovered that the patientsoften experience considerable discomfort at about the time the next oraldose of the opioid is administered.

It has now been surprisingly discovered that quicker and greateranalgesic efficacy is achieved by 24 hour oral opioid formulations whichdo not exhibit a substantially flat serum concentration curve, but whichinstead provide a more rapid initial opioid release so that the minimumeffective analgesic concentration can be more quickly approached in manypatients who have measurable if not significant pain at the time ofdosing. Even at steady-state dosages of oral opioid analgesics, mostpatients have been found to remain in measurable or significant pain andwould benefit greatly from treatment with the novel approach to oralopioid treatment disclosed herein. Also surprising and unexpected is thefact that while the methods of the present invention achieve quicker andgreater analgesic efficacy, there is not a significantly greaterincidence in side effects which would norm ally be expected as higherpeak plasma concentrations occur.

Defining effective analgesic plasma opioid (e.g., morphine) levels isvery complex. However, there is generally a “minimally effectiveanalgesic concentration” (MEAC) in plasma for a particular opioid belowwhich no analgesia is provided. While there is an indirect relationshipbetween, e.g., plasma morphine levels and analgesia, higher plasmalevels are generally associated with superior pain relief. There is alag time or hysteresis, between the time of peak plasma opioid levelsand the time of peak drug effects. This holds true for the treatment ofpain with opioid analgesics in general.

The inventive sustained release once-a-day formulations may becharacterized by the fact that they are designed to provide an initiallyrapid rate of rise in the plasma concentration of said opioidcharacterized by providing an absorption half-life from about 1 to about8 hours, when the oral sustained release formulation is administered inthe fasted state (i.e., without food). In certain embodiments, theabsorption half-life is preferably from about 1 to about 6 hours, andmore preferably from about 1 to about 3 hours.

The inventive formulations may be further characterized by having asurprisingly fast time to peak drug plasma concentration (i.e.,t_(max)). The t_(max) of the sustained release formulations of thepresent invention may be from about 2 to about 10 hours. In certainpreferred embodiments, the t_(max) provided by these formulations may befrom about 4 to about 9 hours.

The administration of 24-hour opioid oral sustained release formulationsin accordance with the present invention reveals a greater degree ofintensity of certain pharmacodynamic endpoints during the earlierportions of the plasma concentration curve (e.g., 4-8 hours after oraladministration), such as sedation respiratory rate, pupil size, and/orcombined scores from a questionnaire of opioid effects reported by thesubjects at serial times following each treatment (i.e., administrationof the oral dosage form). Other measures of analgesic efficacy such assum of pain intensity difference (SPID) and total pain relief (TOTPAR)have consistently higher numerical scores via the presently claimedmethods, while also generating in many cases fewer adverse events (whichin general are predominantly mild or moderate somnolence, nausea and/ordizziness).

Opioid analgesic compounds which may be used in the present inventioninclude alfentanil, allylprodine, alphaprodine, anileridine,benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene,codeine, cyclazocine, desomorphine, dextromoramide, dezocine,diampromide, dihydrocodeine, dihydromorphine, dimenoxadol,dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone,eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine,etonitazene fentanyl, heroin, hydrocodone, hydromorphone,hydroxypethidine, isomethadone, ketobemidone, levallorphan, levorphanol,levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine,methadone, metopon, morphine, myrophine, nalbuphline, narceine,nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine,norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine,phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine,piritramide, propheptazine, promedol, properidine, propiram,propoxyphene, sufentanil, tramadol, tilidine, salts thereof, mixtures ofany of the foregoing, mixed mu-agonists/antagonists, mu-antagonistcombinations, and the like. The opioid analgesic may be in the form ofthe free base, a salt, a complex, etc. In certain preferred embodiments,the opioid analgesic is selected from the group consisting ofhydromorplione, oxycodolle, dihydrocodeine, codeine, dihydromorphine,morphine, buprenorphine, salts of any of the foregoing, and mixtures ofany of the foregoing.

In one preferred embodiment the sustained-release opioid oral dosageform of the present invention includes hydromorphone as thetherapeutically active ingredient in an amount from about 4 to about 64mg hydromorphone hydrochloride. In another preferred embodiment, theopioid analgesic comprises morphine, and the sustained release oraldosage forms of the present invention include form about 5 mg to about800 mg morphine, by weight. Alternatively, the dosage form may containmolar equivalent amounts of other hydromorphone or morphine salts or ofthe base. In certain preferred embodiments wherein the opioid ismorphine, the maximum plasma concentration is from about 2 ng/ml toabout 14 ng/ml, and preferably is from about 3 ng/ml to about 8 ng/ml,based on a 30 mg dose of morphine sulfate. In another preferredembodiment, the opioid analgesic comprises oxycodone, the sustainedrelease oral dosage forms of the present invention include from about 5mg to about 400 mg oxycodone. In other preferred embodiments, the dosageform contains an appropriate amount of another of the opioid analgesicsto provide a substantially equivalent therapeutic effect.

The sustained release dosage forms of the present invention generallyachieve and maintain therapeutic levels substantially withoutsignificant increases in the intensity and/or degree of concurrent sideeffects, such as nausea, vomiting or drowsiness, which are oftenassociated with high blood levels of opioid analgesics. There is alsoevidence to suggest that the use of the present dosage forms leads to areduced risk of drug addiction. Furthermore, the sustained releasedosage forms of the present invention preferably releases the opioidanalgesic at a rate that is independent of pH, e.g., between p1.6 and7.2. In other words, the dosage forms of the present invention avoid“dose dumping” upon oral administration.

In the present invention, the oral opioid analgesics have beenformulated to provide for an increased duration of analgesic actionallowing once-daily dosing. Surprisingly, these formulations, atcomparable daily dosages of conventional immediate release drug, areassociated with a lower incidence in severity of adverse drug reactionsand can also be administered at a lower daily dose than conventionaloral medication while maintaining pain control.

The retardant material utilized in the sustained release formulations ofthe invention may be one which is known in the art, including but notlimited to acrylic polymers, alkylcelluloses, shellac, zein,hydrogenated vegetable oil, hydrogenated castor oil, and mixtures of anyof the foregoing.

In certain preferred embodiments of the present invention, the sustainedrelease opioid dosage forms comprise a plurality of substratescomprising the active ingredient, which substrates are coated with asustained release coating comprising a retardant material. The coatingformulations of the present invention should be capable of producing astrong, continuous film that is smooth and elegant, capable ofsupporting pigments and other coating additives, non-toxic, inert, andtack-free.

The sustained release preparations of the present invention may be usedin conjunction with any multiparticulate system, such as beads,spheroids, microspheres, seeds, pellets, ion-exchange resin beads, andother multi-particulate systems in order to obtain a desired sustainedrelease of the therapeutically active agent. Beads, granules, spheroids,or pellets, etc., prepared in accordance with the present invention canbe presented in a capsule or in any other suitable unit dosage form.

When the substrates of the present invention are inert pharmaceuticalbeads, the inert pharmaceutical beads may be from about 8 mesh to about50 mesh. In certain preferred embodiments, the beads are, e.g., nupariel 18/20 beads.

In certain preferred embodiments of the present invention, the sustainedrelease opioid dosage forms comprise a plurality of substratescomprising the active ingredient, which substrates are coated with asustained release coating. The coating formulations of the presentinvention should be capable of producing a strong, continuous film thatis smooth and elegant, capable of supporting pigments and other coatingadditives, non-toxic, inert, and tack-free.

In order to obtain a sustained release of the opioid sufficient toprovide an analgesic effect for the extended durations set forth in thepresent invention, the substrate comprising the therapeutically activeagent may be coated with a sufficient amount of hydrophobic material toobtain a weight gain level from about 2 to about 30 percent, althoughthe overcoat may be greater depending upon the physical properties ofthe particular opioid analgesic compound utilized and the desiredrelease rate, among other things.

In order to obtain a sustained release of the opioid sufficient toprovide an analgesic effect for the extended durations set forth in thepresent invention, the substrate comprising the therapeutically activeagent may be coated with a sufficient amount of retardant material toobtain a weight gain level from about 2 to about 30 percent, althoughthe overcoat may be greater depending upon the physical properties ofthe particular opioid analgesic compound utilized and the desiredrelease rate, among other things.

The solvent which is used for the retardant material, which is typicallyhydrophobic, may be any pharmaceutically acceptable solvent, includingwater, methanol, ethanol, methylene chloride and mixtures thereof. It ispreferable however, that the coatings be based upon aqueous dispersionsof the hydrophobic material.

In certain preferred embodiments of the present invention, thehydrophobic polymer comprising the sustained release coating is apharmaceutically acceptable acrylic polymer, including but not limitedto acrylic acid and methacrylic acid copolymers, methyl methacrylatecopolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate,aminoalkyl methacrylate copolymer, poly(acrylic acid), poly(methacrylicacid), methacrylic acid alkylamide copolymer, poly(methyl methacrylate),poly(methacrylic acid anhydride), methyl methacrylate, polymethacrylate,poly(methyl methacrylate) copolymer, polyacrylamide, aminoalkylmethacrylate copolymer and glycidyl methacrylate copolymers.

In certain preferred embodiments, the acrylic polymer is comprised ofone or more ammonio methacrylate copolymers. Ammonio methacrylatecopolymers are well known in the art, and are described in NF XVII asfully polymerized copolymers of acrylic and methacrylic acid esters witha low content of quaternary ammonium groups.

In one preferred embodiment, the acrylic coating is an acrylic resinlacquer used in the form of an aqueous dispersion, such as that which iscommercially available from Rohm Pharma under the Tradename Eudragit®.In further preferred embodiments, the acrylic coating comprises amixture of two acrylic resin lacquers commercially available from RohmPharma under the Tradenames Eudragit® RL 30 D and Eudragit® RS 30 D,respectively. Eudragit® RL 30 D and Eudragit® RS 30 D are copolymers ofacrylic and methacrylic esters with a low content of quaternary ammoniumgroups, the molar ratio of ammonium groups to the remaining neutral(meth)acrylic esters being 1:20 in Eudragit® RL 30 D and 1:40 inEudragit® RS 30 D. The mean molecular weight is about 150,000. The codedesignations RL (high permeability) and RS (low permeability) refer tothe permeability properties of these agents. Eudragit® RL/RS mixturesare insoluble in water and in digestive fluids. However, coatings formedfrom the same are swellable and permeable in aqueous solutions anddigestive fluids.

The Eudragit® RL/RS dispersions of the present invention may be mixedtogether in any desired ratio in order to ultimately obtain a sustainedrelease formulation having a desirable dissolution profile. Desirablesustained release formulations may be obtained, for instance, from aretardant coating derived from 100% Eudragit® RL, 50% Eudragit® RL and50% Eudragit® RS, and 10% Eudragit® RL:Eudragit® 90% RS. Of course, oneskilled in the art will recognize that other acrylic polymers may alsobe used, such as, for example, Eudragit® L.

In other preferred embodiments, the hydrophobic polymer which may beused for coating the substrates of the present invention is ahydrophobic alkyl cellulosic material such as ethylcellulose. Thoseskilled in the art will appreciate that other cellulosic polymers,including other alkyl cellulosic polymers, may be substituted for partor all of the ethylcellulose included in the hydrophobic polymercoatings of the present invention.

One commercially available aqueous dispersion of ethylcellulose isAquacoat® (FMC Corp., Philadelphia, Pa., U.S.A.). Aquacoat® is preparedby dissolving the ethylcellulose in a water-immiscible organic solventand then emulsifying the same in water in the presence of a surfactantand a stabilizer. After homogenization to generate submicron droplets,the organic solvent is evaporated under vacuum to form a pseudolatex.The plasticizer is not incorporated in the pseudolatex during themanufacturing phase. Thus, prior to using the same as a coating, it isnecessary to intimately mix the Aquacoat® with a suitable plasticizerprior to use.

Another aqueous dispersion of ethylcellulose is commercially availableas Surelease® (Colorcon, Inc., West Point, Pa., U.S.A.). This product isprepared by incorporating plasticizer into the dispersion during themanufacturing process. A hot melt of a polymer, plasticizer (dibutylsebacate), and stabilizer (oleic acid) is prepared as a homogeneousmixture, which is then diluted with an alkaline solution to obtain anaqueous dispersion which can be applied directly onto substrates.

In embodiments of the present invention where the coating comprises anaqueous dispersion of a hydrophobic polymer, the inclusion of aneffective amount of a plasticizer in the aqueous dispersion ofhydrophobic polymer will further improve the physical properties of thefilm. For example, because ethylcellulose has a relatively high glasstransition temperature and does not form flexible films under normalcoating conditions, it is necessary to plasticize the ethylcellulosebefore using the same as a coating material. Generally, the amount ofplasticizer included in a coating solution is based on the concentrationof the film-former, e.g., most often from about 1 to about 50 percent byweight of the film-former. Concentration of the plasticizer, however,can only be properly determined after careful experimentation with theparticular coating solution and method of application.

Examples of suitable plasticizers for ethylcellulose include waterinsoluble plasticizers such as dibutyl sebacate, diethyl phthalate,triethyl citrate, tributyl citrate, and triacetin, although it ispossible that other water-insoluble plasticizers (such as acetylatedmonoglycerides, phthalate esters, castor oil, etc.) may be used.Triethyl citrate is especially preferred.

Examples of suitable plasticizers for the acrylic polymers of thepresent invention include citric acid esters such as triethyl citrate NFXVI, tributyl citrate, dibutyl phthalate, and possibly 1,2-propyleneglycol, polyethylene glycols, propylene glycol, diethyl phthalate,castor oil, and triacetin, although it is possible that otherwater-insoluble plasticizers (such as acetylated monoglycerides,phthalate esters, castor oil, etc.) may be used. Triethyl citrate isespecially preferred.

The sustained release profile of the formulations of the invention canbe altered, for example, by varying the thickness of the hydrophobiccoating, changing the particular hydrophobic material used, or alteringthe relative amounts of, e.g., different acrylic resin lacquers,altering the manner in which the plasticizer is added (e.g., when thesustained release coating is derived from an aqueous dispersion ofhydrophobic polymer), by varying the amount of plasticizer relative tohydrophobic polymer, by the inclusion of additional ingredients orexcipients, by altering the method of manufacture, etc.

Sustained release spheroids or beads, coated with an opioid may beprepared, e.g. by dissolving the opioid analgesic in water and thenspraying the solution onto a substrate, for example, nu pariel 18/20beads, using a Wurster insert. Optionally, additional ingredients arealso added prior to coating the beads in order to assist the opioidbinding to the substrates, and/or to color the solution, etc. Forexample, a product which includes hydroxypropyl methylcellulose, etc.with or without colorant may be added to the solution and the solutionmixed (e.g., for about 1 hour) prior to application of the same onto thebeads. The resultant coated substrate, in this example beads, may thenbe optionally overcoated with a barrier agent, to separate thetherapeutically active agent from the hydrophobic sustained releasecoating. An example of a suitable barrier agent is one which compriseshydroxypropyl methylcellulose. However, any film-former known in the artmay be used. It is preferred that the barrier agent does not affect thedissolution rate of the final product.

The opioid, HPMC protected (optional) beads may then be overcoated withhydrophobic polymer, preferably with an effective amount of plasticizer.

The coating solutions of the present invention preferably contain, inaddition to the film-former, plasticizer, and solvent system (i.e.,water), a colorant to provide elegance and product distinction. Colormay be added to the solution of the therapeutically active agentinstead, or in addition to the aqueous dispersion of hydrophobicpolymer.

The plasticized aqueous dispersion of hydrophobic polymer may be appliedonto the substrate comprising the therapeutically active agent byspraying using any suitable spray equipment known in the art. In apreferred method, a Wurster fluidized-bed system is used in which an airjet, injected from underneath, fluidizes the core material and effectsdrying while the acrylic polymer coating is sprayed on. A sufficientamount of the aqueous dispersion of hydrophobic polymer to obtain apredetermined sustained-release of said therapeutically active agentwhen said coated substrate is exposed to aqueous solutions, e.g. gastricfluid, is preferably applied, talking into account the physicallycharacteristics of the therapeutically active agent, the manner ofincorporation of the plasticizer, etc. After coating with thehydrophobic polymer, a further overcoat of a film-former, such asOpadry®, is optionally applied to the beads. This overcoat is provided,if at all, in order to substantially reduce agglomeration of the beads.

Next, the coated beads are cured in order to obtain a stabilized releaserate of the therapeutically active agent.

When the coating comprises an aqueous dispersion of ethylcellulose, thecoated substrate is preferably subjected to curing at a temperaturegreater than the glass transition temperature of the coating solution(i.e., ethylcellulose) and at a relative humidity from about 60% toabout 100%, until the curing endpoint is reached, e.g., about 60° C. anda relative humidity from about 60% to about 100% for a time period fromabout 48 to about 72 hours, as described in U.S. Pat. No. 5,273,760,hereby incorporated by reference.

In preferred embodiments of the present invention directed to theacrylic coating, a stabilized product is obtained by subjecting thecoated substrate to oven curing at a temperature above the Tg of theplasticized acrylic polymer for the required time period, the optimumvalues for temperature and time for the particular formulation beingdetermined experimentally. In certain embodiments of the presentinvention, the stabilized product is obtained via an oven curingconducted at a temperature of about 45° C. for a time period from about24 to about 48 hours or longer, as described in U.S. Pat. No. 5,286,493,hereby incorporated by reference.

The release of the therapeutically active agent from thesustained-release formulation of the present invention can be furtherinfluenced, i.e., adjusted to a desired rate, by the addition of one ormore release-modifying agents, or by providing one or more passagewaysthrough the coating. The ratio of hydrophobic polymer to water solublematerial is determined by, among other factors, the release raterequired and the solubility characteristics of the materials selected.

The release-modifying agents which function as pore-formers may beorganic or inorganic, and include materials that can be dissolved,extracted or leached from the coating in the environment of use. Thepore-formers may comprise one or more hydrophilic polymers such ashydroxypropylmethylcellulose. The sustained release coatings of thepresent invention can also include erosion-promoting agents such asstarch and gums. The sustained release coatings of the present inventioncan also include materials useful for making microporous lamina in theenvironment of use, such as polycarbonates comprised of linearpolyesters of carbonic acid in which carbonate groups reoccur in thepolymer chain. The release-modifying agent may also comprise asemi-permeable polymer. In certain preferred embodiments, therelease-modifying agent is selected from hydroxypropylmethylcellulose,lactose, metal stearates, and mixtures of any of the foregoing. Thesustained release coatings of the present invention may also include anexit means comprising at least one passageway, orifice, or the like. Thepassageway may be formed by such methods as those disclosed in U.S. Pat.Nos. 3,845,770; 3,916,889; 4,063,064; and 4,088,864 (all of which arehereby incorporated by reference). The passageway can have any shapesuch as round, triangular, square, elliptical, irregular, etc.

In other embodiments of the present invention, the present invention mayutilize a multiparticulate sustained release matrix. Suitable materialsfor inclusion in a sustained release matrix are

(a) Hydrophilic polymers, such as gums, cellulose ethers, acrylic resinsand protein derived materials. Of these polymers, the cellulose ethers,especially hydroxyalkylcelluloses and carboxyalkylcelluloses, arepreferred. The oral dosage form may contain between 1% and 80% (byweight) of at least one hydrophilic or hydrophobic polymer.

(b) Digestible, long chain (C₈C₅₀, especially C₁₂-C₄₀), substituted orunsubstituted hydrocarbons, such as fatty acids, fatty alcohols,glyceryl esters of fatty acids, mineral and vegetable oils and waxes.Hydrocarbons having a melting point of between 25° and 90° C. arepreferred of these long chain hydrocarbon materials, fatty (aliphatic)alcohols are preferred. The oral dosage form may contain up to 60% (byweight) of at least one digestible, long chain hydrocarbon.

(c) Polyalkylene glycols. The oral dosage form may contain up to 60% (byweight) of at least one polyalkylene glycol.

For example, a suitable matrix may be one which comprises at least onewater soluble hydroxyalkyl cellulose, at least one C₁₂-C₃₆, preferablyC₁₄-C₂₂, aliphatic alcohol and, optionally, at least one polyalkyleneglycol. The at least one hydroxyalkyl cellulose is preferably a hydroxy(C₁ to C₆) alkyl cellulose, such as hydroxypropylcellulose,hydroxypropylmethylcellulose and, especially, hydroxyethyl cellulose.The amount of the at least one hydroxyalkyl cellulose in the presentoral dosage form will be determined, inter alia, by the precise rate ofopioid release required. The at least one aliphatic alcohol may be, forexample, lauryl alcohol, myristyl alcohol or stearyl alcohol. In certainpreferred embodiments, the at least one aliphatic alcohol is cetylalcohol or cetostearyl alcohol. The amount of the at least one aliphaticalcohol in the present oral dosage form will be determined, as above, bythe precise rate of opioid release required. It will also depend onwhether at least one polyalkylene glycol is present in or absent fromthe oral dosage form. In the absence of at least one polyalkyleneglycol, the oral dosage form preferably contains between 20% and 50% (bywt) of the at least one aliphatic alcohol. When at least onepolyalkylene glycol is present in the oral dosage form, then thecombined weight of the at least one aliphatic alcohol and the at leastone polyalkylene glycol preferably constitutes between 20% and 50% (bywt) of the total dosage.

In one embodiment, the ratio of, e.g., at least one hydroxyalkylcellulose or acrylic resin to at least one aliphaticalcohol/polyalkylene glycol determines, to a considerable extent, therelease rate of the opioid from the formulation. A ratio of the at leastone hydroxyalkyl cellulose to at least one aliphatic alcohol/polyalkylene glycol of between 1:2 and 1:4 is preferred, with a ratio ofbetween 1:3 and 1:4 being particularly preferred.

At least one polyalkylene glycol may be, for example, polypropyleneglycol or, preferably, polyethylene glycol. The number average molecularweight of the at least one polyalkylene glycol is preferred between 1000and 15000 especially between 1500 and 12000.

Another suitable sustained release matrix would comprise analkylcellulose (especially ethyl cellulose), a C₁₂ to C₃₆ aliphaticalcohol and, optionally, a polyalkylene glycol.

In addition to the above ingredients, a sustained release matrix mayalso contain suitable quantities of other materials, e.g., diluents,lubricants, binders, granulating aids, colorants, flavorants andglidants that are conventional in the pharmaceutical art.

These sustained release matrices may be prepared, for example, by

(a) forming granules comprising at least one water soluble hydroxyalkylcellulose and opioid or an opioid salt,

(b) mixing the hydroxyalkyl cellulose containing granules with at leastone C₁₂-C₃₆ aliphatic alcohol, and

(c) optionally, compressing and shaping the granules. Preferably, thegranules are formed by wet granulating the hydroxyalkyl cellulose/opioidwith water. The amount of water added during the wet granulation stepmay be, e.g., between 1.5 and 5 times, especially between 1.75 and 3.5times, the dry weight of the opioid.

In yet other alternative embodiments, a spheronizing agent, togetherwith the active ingredient can be spheronized to form spheroids.Microcrystalline cellulose is preferred, although hydrous lactoseimpalpable is preferably utilized for morphine sulfate sustained releaseformulations prepared by powder-layering techniques. A suitablemicrocrystalline cellulose is, for example, the material sold as AvicelPH 101 (Trade Mark, FMC Corporation). In such embodiments, in additionto the active ingredient and spheronizing agent, the spheroids may alsocontain a binder. Suitable binders, such as low viscosity, water solublepolymers, will be well known to those skilled in the pharmaceutical art.However, water soluble hydroxy lower alkyl cellulose, such as hydroxypropyl cellulose, are preferred. Additionally (or alternatively) thespheroids may contain a water insoluble polymer, especially an acrylicpolymer, an acrylic copolymer, such as a methacrylic acid-ethyl acrylatecopolymer, or ethyl cellulose. In such embodiments, the sustainedrelease coating will generally include a water insoluble material suchas (a) a wax, either alone or in admixture with a fatty alcohol; or (b)shellac or zein.

The substrates of the present invention may also be prepared via a meltpellitization technique. In such circumstance, the opioid in finelydivided form is combined with a binder (also in particulate form) andother optional inert ingredients, and thereafter the mixture ispelletized, e.g., by mechanically working the mixture in a high shearmixer to form the pellets (granules, spheres). Thereafter, the pellets(granules, spheres) may be sieved in order to obtain pellets of therequisite size. The binder material is preferably in particulate formand has a melting point above about 40° C. Suitable binder substancesinclude, for example, hydrogenated castor oil, hydrogenated vegetableoil, other hydrogenated fats, fatty alcohols, fatty acid esters, fattyacid glycerides, and the like.

In certain preferred embodiments of the present invention, an effectiveamount of opioid in immediate release form is included in the 24 hoursustained release unit dose opioid formulation to be administered. Theimmediate release form of the opioid is included in an amount which iseffective to shorten the time to maximum concentration of the opioid inthe blood (e.g., plasma). In such embodiments, an effective amount ofthe opioid in immediate release form may be coated onto the substratesof the present invention. For example, where the extended release opioidfrom the formulation is due to a controlled release coating, theimmediate release layer would be overcoated on top of the controlledrelease coating. On the other hand, the immediate release layer may becoated onto the surface of substrates wherein the opioid is incorporatedin a controlled release matrix. Where a plurality of the sustainedrelease substrates comprising an effective unit dose of the opioid(e.g., multiparticulate systems including pellets, spheres, beads andthe like) are incorporated into a hard gelatin capsule, the immediaterelease portion of the opioid dose may be incorporated into the gelatincapsule via inclusion of the sufficient amount of immediate releaseopioid as a powder or granulate within the capsule. Alternatively, thegelatin capsule itself may be coated with an immediate release layer ofthe opioid. One skilled in the art would recognize still otheralternative manners of incorporating the immediate release opioidportion into the unit dose. Such alternatives are deemed to beencompassed by the appended claims. It has been discovered that byincluding such an effective amount of immediate release opioid in theunit dose, the experience of relatively higher levels of pain inpatients is significantly reduced.

The dosage form may be provided by preparing a dosage form consistentwith one of the above described methods or by other means known to thoseskilled in the pharmaceutical art.

In addition to the above, the sustained release opioid formulations mayalso be manufactured as tablets. In such instances, the tablet maycontain, in addition to the opioid and the retardant material, suitablequantities of other materials, e.g. diluents, lubricants, binders,granulating aids, colorants, flavorants and glidants that areconventional in the pharmaceutical art in amounts up to about 50% byweight of the particulate if desired. Specific examples ofpharmaceutically acceptable carriers and excipients that may be used toformulate oral dosage forms are described in the Handbook ofPharmaceutical Excipients, American Pharmaceutical Association (1986),incorporated by reference herein. Techniques and compositions for makingsolid oral dosage forms are described in Pharmaceutical Dosage Forms:Tablets (Lieberman, Lachman and Schwartz, editors) Second Edition,published by Marcel Dekker, Inc., incorporated by reference herein.Techniques and compositions for making tablets (compressed and molded),capsules (hard and soft gelatin) and pills are also described inRemington's Pharmaceutical Sciences, (Arthur Osol, editor), 1553-1593(1980), incorporated by reference herein.

In order to titrate a human patient with the inventive sustained releaseopioid formulations, a plurality of blood samples are taken from thepatient over the course of the dosing interval. The samples thusobtained are then tested to determine the plasma level of the opioidanalgesic, and any active metabolites thereof. The values thus obtainedmay then be utilized to determine additional pharmacokinetic parameters.A determination as to whether the patient has obtained an adequatepharmacodynamic response with said dosage form will be made, e.g.,reference to predetermined blood levels, comparison of the resultssubjective pain tests given to the patient, the adverse effect profileof the drug in he patient, or the like. A determination may then be madeas to whether an upward or downward adjustment of the dose is necessary.

The administration of the sustained release unit dosage form iscontinued over the dosing interval of the unit dose to maintain anadequate pharmacodynamic response with the sustained release dosageform. Preferably the adequate pharmacodynamic response will last betweenabout 12 and about 24 hours, most preferably about 24 hours or greater.

The administration of the sustained release unit dosage form iscontinued over the dosing interval of the unit dose to maintain saidadequate pharmacodynamic response with said sustained release dosageform.

If necessary, the above steps are repeated until a determination ofadequate pharmacodynamic response is obtained with the sustained releaseunit dosage form.

According to the above method, a patient may be titrated with asustained release opioid analgesic dosage form. Subsequent maintenancetherapy may be provided with the same sustained release dosage form.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The following examples illustrate various aspects of the presentinvention. They are not to be construed to limit the claims in anymanner whatsoever.

EXAMPLES 1-2

In Example 1, morphine sulfate sustained-release beads with a 5% w/wsustained release coating comprising Eudragit® RS were prepared,including a 10% immediate release morphine sulfate overcoat. In Example2, morphine sulfate sustained-release beads with an 8% w/wsustained-release coating comprising Eudragit® RS were prepared,including a 10% immediate release morphine sulfate overcoat.

Morphine sulfate beads were first manufactured using a rotor processingtechnique. The formula of the morphine sulfate beads to which thesustained-release coating was applied is set forth in Table 1 below:TABLE 1 Amt/Unit Ingredient (mg) Percent (%) Morphine Sulfate Powder 30mg 14.3% Lactose Hydrous Impalpable 42.5 mg 20.2% PVP 2.5 mg 1.2% SugarBeads 18/20 125 mg 59.4% Purified Water qs mg — Opadry Red YS-1-184110.5 mg 4.9% Total 210.5 mg 100.0%

A sustained-release coating was then applied to the morphine sulfatebeads. The formula for the sustained release coating of Examples 1 and 2is set forth in Table 2 below: TABLE 2 Example 1 Example 2 Ingredient(mg) % (mg) % Retardant Coating Morphine Base Beads 189.45 mg 86.7%189.5 mg 83.0% Eudragit RS 30D 9.5 mg 4.3% 15.2 mg 6.7% Triethyl Citrate1.9 mg 0.9% 3.0 mg 1.3% Talc 3.8 mg 1.7% 6.1 mg 2.7% Purified Water qs —qs — Overcoat Morphine Sulfate 3.0 mg 1.4% 3.0 mg 1.3% Powder Opadry Red10.8 mg 5.0% 11.4 mg 5.0% YS-1-1841 Purified Water qs — qs — Total218.45 mg 100.0% 228.2 mg 100.0%

The sustained-release coating was manufactured as follows. The EudragitRS30D was plasticized with triethyl citrate and talc for approximately30 minutes. A load of the morphine sulfate beads was charged into aWurster Insert of a Glatt equipped with a 1.2 mm spray nozzle and thebeads were coated to a weight gain of 5% and 8% for Examples 1 and 2,respectively. The final protective Opadry dispersion overcoat was thenapplied in the Wurster Insert. Upon completion the beads were cured fortwo days in a dry oven of 45° C. The cured beads were then filled intogelatin capsules at a 30 mg strength.

Dissolution testing was conducted on the gelatin capsules via U.S.P.Apparatus II (Paddle Method). The capsules were placed into 700 ml ofsimulated gastric fluid (without enzymes) for the first hour at 100 rpmand 37° C., and then placed into 900 ml of simulated gastric fluid(without enzymes) after the first hour. The results of the percent ofmorphine sulfate dissolved in relation to time for Examples 1 and 2 areset forth in Table 3 below: TABLE 3 Percent Morphine Sulfate DissolvedTime Example 1 Example 2  1 hour 11.9% 10.2%  2 hours 15.4% 11.3%  4hours 28.1% 12.8%  8 hours 58.3% 16.4% 12 hours 79.2% 29.6% 18 hours92.0% 58.1% 24 hours 96.6% 73.2%Clinical Evaluation of Examples 1-2

Ten normal, healthy male subjects were enrolled in a four-way,randomized, single-dose, crossover pharmacokcinetic/pharmacodynamicstudy to characterize the effect of food on thepharmacokinetic/pharmacodynamic profile of Example 1 compared with thesame product and with morphine CR 30 mg tablet (MS Contin®), each in thefasted state, using plasma morphine concentration and pharmacodynamicparameters. A comparison of Example 2 with morphine controlled release30 mg tablet (MS Contin®) was also made. Plasma morphine concentrationswere used for calculation of pharmacokinetic parameters including: (a)absorption and elimination rates; (b) area under the curve (AUC); (c)maximum plasma concentration (C_(max)); (d) time to maximum plasmaconcentration T_(max)); (e) T_(1/2) (elimination). Pharmacodynamiceffect compared with plasma concentrations of morphine was to bedescribed from data obtained from the following pharmacodynamicparameters: mood, sedation, respiratory rate, pupillometry and anadjective questionnaire.

Clinical Laboratory Evaluations

Blood samples were collected for hematology (hemoglobin, hematocrit, redblood cell count, white blood cell count with differential, plateletcount) and blood chemistry analyses (calcium, inorganic phosphate, uricacid, total protein, albumin, cholesterol, alkaline phosphatase, lactatedehydrogenase (LDH), total bilirubin, serum glutamic oxaloacetictransaminase (SGOT), serum glutainic pyruvate transaminase (SGPT),fasting blood glucose, blood urea nitrogen (BUN), serum creatinine) pre-and post- (72 hours) study (i.e., 72 hours after Phase 4 dose). A urinesample was collected for urinalysis (specific gravity, glucose, albumin,bile, pH, acetone, microscopic examination) pre- and post- (72 hours)study (i.e., 72 hours after Phase 4 dose). A pre-study urinalysis forillicit drugs was performed during the screening process and immediatelypre-dose for each administration of the study drug (Day 1 of Phases 1through 4).

Plasma morphine concentrations were determined from blood samples whichwere drawn just prior to dosing (0 hour) and thereafter at 0.5, 1, 2,2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48 and 72 hours followingeach dose. Blood samples, each approximately 10 ml, were drawn intotubes containing ethylenediaminetetraacetic acid (EDTA) solution, ananticoagulant. Following centrifugation, the plasma was pipetted intotwo 5-ml polypropylene, labeled tubes and frozen at −20° C. One set ofsamples was shipped to the designated analytical laboratory insufficient dry ice to keep them frozen for 2 days, and the second setwas retained frozen at the study site as a back-up.

Pharmacodynamic Measurements

Measurements of the following pharmacodynamic parameters were made justprior to blood sampling at baseline (within 30 minutes prior to dosing)and thereafter at 0.5, 1, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24,36, 48 and 72 hours following each dose.

Mood (measured by a visual analog scale (VAS) on a subject diarysheet)—10 minutes prior to blood sampling. The VAS was anchored on oneend as Worst Mood and the other end as Best Mood.

Sedation (measured by VAS on a subject diary sheet)—10 minutes prior toblood sampling. The VAS was anchored on one end as Asleep and the otherend as Awake.

Respiratory rate (breaths per minute)—within 5 minutes of bloodsampling. (Data were recorded on a subject diary sheet.)

Pupil size—measured by pupillometry—within 5 minutes of blood sampling.Only the left eye was measured at all time periods. (Data were recordedon a subject diary sheet.)

FIG. 1 is a graphical representation of the mean sedation vs. time curvefor Example 1 (fasted). FIG. 2 is a graphical representation of the meansedation vs. time curve for Example 2 (fasted). FIG. 3 is a graphicalrepresentation of the mean respiratory rate vs. time curve for Example 1(fasted). FIG. 4 is a graphical representation of the mean respiratoryrate vs. time curve for Example 2 (fasted).

Plasma morphine concentrations were determined by a high-performanceliquid chromatographic procedure. Arithmetic mean Cmax, Tmax, AUC,half-lives calculated from individual plasma morphineconcentration-versus-time, and oral bioavailability data were as setforth in Tables 4 and 5 below: TABLE 4 Pharmacokinetic MS Contin ® Ex. 2Ex. 1 Parameter (Fast) (Fast) (Fast) (Fed) C_(max) (ng/ml) 13.05 3.95*5.42* 5.87* T_(max) (hours) 2.45 15.05* 5.85 6.90 AUC (0.72) 101.11136.10* 109.37 111.33 (hr-ng/ml) AUC (0.00) 101.31 155.44* 117.77 114.45(hr-ng/ml) T_(1/2) (elim; hrs) 2.81 89.68* 19.02 10.34 T_(1/2) (abs;hrs) 1.20 3.96 2.51 3.48

TABLE 5 F₀ (%) F₀ (%) F₀ (%) F₀ (%) Pharmacokinetic 90% C.I. 90% C.I.90% C.I. 90% C.I. Parameter (B vs. A) (C vs. A) (D vs. A) (D vs. C)C_(max)  32.24  39.88  42.50 106.57 (ng/ml) (15.7-48.7) (23.3-56.5)(26.0-59.0) (65.2-148.0) T_(max) 608.27 232.33 290.48 125.03 (hours)(435.6-780.9)  (58.8-405.8)  (117.9-463.11) (50.7-199.3) AUC 134.53105.02 106.04 100.97 (0.72) (111.1-158.0)  (81.5-128.6)  (82.6-129.5)(78.6-123.3) (hr-ng/ml) AUC 151.04 112.91 108.09  95.73 (0.00)(112.6-189.4)  (81.8-144.0)  (77.1-139.0) (68.3-123.1) (hr-ng/ml)T_(1/2) (elim; 3076.7  689.41 374.01  54.25 hrs) (2256.7-3896.7) (24.9-1353.9) (−286.8-1034.9) (−41.6-150.1)   T_(1/2) (abs; 281.21167.18 239.86 143.48 hrs) (−123.1-685.5)   (−11.7-346.0)  (62.4-417.3)(37.2-249.8)*Statistically significant (p < .0500) when compared to MS Contin ®(based on untransformed data)F₀ (%) = Oral bioavailability (Test least squares mean/Reference leastsquares mean)(A = MS Contin; B = Example 2 fasted; C = Example 1 Fed; and D = Example1 fasted)

Table 6 provides the mean (±S.D.) plasma morphine concentrations (ng/ml)following dosing with MS Contin® and Examples 1 and 2. TABLE 6 Mean(±S.D.) Plasma Morphine Concentrations (ng/ml) Following Dosing With MSContin ® And Each Formulation Of Morphine Beads Time MS Contin ® Ex. 2Ex. 1 Ex. 1 (hours) 30 mg (Fast) (Fast) (Fast) (Fed) 0.00 0.00 ± 0.000.00 ± 0.00 0.00 ± 0.00 0.00 ± 0.00 0.50 3.04 ± 2.07 2.22 ± 1.09 1.82 ±1.35 0.51 ± 0.79 1.00 6.78 ± 4.19 1.89 ± 0.54 2.09 ± 1.07 1.46 ± 0.952.00 11.43 ± 5.70  1.60 ± 0.69 2.33 ± 0.98 2.46 ± 0.91 2.50 10.30 ±6.46  1.78 ± 1.16 2.22 ± 0.88 2.51 ± 0.88 3.00 9.40 ± 5.41 1.54 ± 0.972.61 ± 1.12 3.47 ± 1.77 3.50 8.09 ± 4.48 1.34 ± 0.98 2.82 ± 1.39 3.03 ±1.26 4.00 7.11 ± 3.78 1.06 ± 0.49 3.60 ± 2.50 3.41 ± 1.82 5.00 7.25 ±4.71 1.54 ± 1.21 4.09 ± 2.24 3.80 ± 1.29 6.00 5.27 ± 3.31 1.20 ± 0.774.11 ± 1.74 4.23 ± 1.68 8.00 3.19 ± 1.99 1.58 ± 1.00 3.80 ± 1.46 4.46 ±1.51 10.0 1.87 ± 1.00 2.62 ± 1.05 3.57 ± 1.44 4.16 ± 1.37 12.0 1.70 ±0.76 3.10 ± 1.64 2.83 ± 0.64 4.33 ± 2.20 18.0 1.23 ± 0.67 3.04 ± 1.112.40 ± 1.13 1.85 ± 1.12 24.0 1.38 ± 0.96 2.54 ± 0.55 1.82 ± 1.01 1.71 ±0.73 36.0 0.85 ± 0.64 2.58 ± 1.04 1.35 ± 0.70 1.19 ± 0.40 48.0 0.22 ±0.47 1.48 ± 0.48 0.69 ± 1.08 0.73 ± 0.56 72.0 0.05 ± 0.16 0.54 ± 0.660.16 ± 0.33 0.22 ± 0.46

Table 7 provides the mean (±S.D.) pharmacokinetic parameters followingdosing with MS Contin® And Examples 1-2. TABLE 7 Mean (±S.D.)Pharmacokinetic Parameters Following Dosing With MS Contin ® And EachFormulation Of Morphine Beads MS Contin ® 30 mg Ex. 2 Ex. 1 Ex. 1Parameter (Fast) (Fast) (Fast) (Fed) C_(max) 13.05 ± 5.22  3.95 ± 1.555.42 ± 2.26 5.87 ± 2.07 (ng/ml) Tmax 2.45 ± 0.86 15.05 ± 9.51  5.85 ±1.92 6.90 ± 3.18 (hrs) AUC(0.72) 101.11 ± 41.913 136.10 ± 34.58  109.37± 43.06  111.33 ± 36.21  (hr-ng/ml)

In comparing Example 1 (fast) to MS Contin® (fast), there was astatistically significant difference in C_(max). There were nostatistically significant differences between the two treatments inT_(max), AUC (0,72), AUC (0, oo) and T_(1/2) (elim) or T_(1/2) (abs).The 90% confidence intervals for all pharmacokinetic parameters wereoutside the 80-120% limits.

In comparing Example 1 (fed) to MS Contin® (fast), there was astatistically significant difference in C_(max). There were nostatistically significant differences between the two treatments inT_(max), AUC (0,72), AUC (0, oo) and T_(1/2) (elim) or T_(1/2) (abs).The 90% confidence intervals for all pharmacokinetic parameters wereoutside the 80-120% limits.

In comparing Example 1 under fed and fasting conditions, there were nostatistically significant differences in C_(max), T_(max), AUC (0,72),AUC (0, oo) and T_(1/2) (elim) or T_(1/2) (abs). The 90% confidenceintervals for all pharmacokinetic parameters were outside the 80-120%limits.

The effect of food on the absorption of Example 1 is characterized by agreater C_(max) and extended T_(max) and T_(1/2) (abs) values. Theextent of absorption (based on AUCs), however, is less than 3% differentunder fed and fasted conditions.

In comparing Example 2 (fast) to MS Contin® (fast), there werestatistically significant differences in C_(max), T_(max), AUC (0,72),AUC (0, oo) and T_(1/2) (elim). There was no statistically significantdifference between the two treatments in T_(1/2) (abs). The 90%confidence intervals for all pharmacokinetic parameters were outside the80-120% limits.

Based on the 90% confidence interval analysis, neither Example 1 underfasted or fed conditions nor Example 2 beads are equivalent to MSContin® tablets. However, while neither of the experimentalcontrolled-release morphine formulations are bioequivalent to MS Contin®tablets, both provide a relatively lower C_(max) and extended T_(max)and apparent T_(1/2) (elim) values.

Linear regression of each pharmacodynamic parameter on thelog-transformed concentrations for each subject and treatment resultedin 48 of 240 regressions (48/240; 20%) having an R² value of 20% orhigher, of which 8 (8/240; 3%) had a value of 50% or higher. Whenanalyzed by treatment only, all R² values were lower than 10%. Thesevalues indicate no significant linear relationship between thepharmacodynamic measurements and the log concentrations.

Examination of the mean hysteresis curves revealed a possiblerelationship between pupil size and morphine concentration. For MSContin® and Example 1, pupil size tended to decrease with an increase inmorphine concentration, then increase as morphine concentrationdecreased. FIG. 5 is a graphical representation of the mean pupil sizev. time curve for Example 1 (fasted). FIG. 6 is a graphicalrepresentation of the mean pupil size vs. time curve for Example 2(fasted). No relationship was observed between morphine concentrationsand any of the other parameters.

Two subjects (20%) reported six adverse experiences while receiving MSContin®. Three subjects (30%) reported six adverse experiences whilereceiving controlled-release morphine beads (Example 1; fasted). Onesubject in each of the following treatment groups reported a singleadverse experience: Example 1 (fed) and Example 2 (fasted). Noclinically significant changes in physical examination or EKG results,clinical laboratory values or vital sign measurements occurred duringthe study.

Modified Specific Drug Effect Questionnaire

The questionnaire was a modification of the 22-item questionnaire usedby Jasinski, D. R. (1977) Assessment of the Abuse Potential ofMorphinie-Like Drugs (Methods Used in Man). In Drug Addiction I (Martin,W. R., ed.) pp. 197-258. Springer-Verlag, New York; and Preston, K. L.,Jasinski, D. R., and Testa, M. (1991) Abuse Potential andPharmacological Comparison of Tramadol and Morphine. Drug and AlcoholDependence 27:7-17. The questionnaire consisted of 10 items to be ratedby the subject and observer. The items were related to signs ofopiate-agonist drugs and were as follows:

Subject's Questions

-   1. Do you feel any effects of the drugs?-   2. Is your skin itchy?-   3. Are you relaxed?-   4. Are you sleepy?-   5. Are you drunk?-   6. Are you nervous?-   7. Are you full of energy?-   8. Do you need to talk?p0 9. Are you sick to your stomach?-   10. Are you dizzy?    The subject rated each of these questions by placing a vertical mark    along a 100-mm VAS anchored at one end by “not at all” and at the    other end by “an awful lot”.    Observer's Questions-   1. Is the subject showing any drug effect?-   2. Is the subject scratching?-   3. Is the subject relaxed?-   4. Is the subject drunk?-   5. Is the subject nervous?-   6. Is the subject talking?-   7. Is the subject vomiting?-   8. Is the subject confused?-   9. Is the subject restless?-   10. Is the subject perspiring?

The observer rated each of these questions by placing a vertical markalong a 100-mm VAS anchored at one end by “not at all” and at the otherend by “extremely”. FIG. 7 is a graphical representation of the meanssubject questionnaire vs. time curve for Example 1 (fasted). FIG. 8 is agraphical representation of the means subject questionnaire vs. timecurve for Example 2 (fasted).

Adverse Experiences

Adverse experiences, whether spontaneously reported or elicited upondirect questioning, were recorded and evaluated promptly by theprincipal investigator to determine the severity, duration andinitiation of corrective measures, if warranted. Subjects were to befollowed until they returned to-baseline status.

Analytical

Plasma morphine analyses were conducted using high performance liquidchromatography (HPLC). The limit of quantification was 0.5 ng/mL.Appendix V contains the plasma morphine analytical report.

Statistical and Pharmacometric Methods

Parameters

The serial plasma morphine values, collected from each subject andtreatment, were corrected for the zero-hour value by subtraction of thezero-hour value from all subsequent values in that series.

Any serial dataset in which the zero-hour value exceeded the minimumassay sensitivity was, as noted above, deemed inadmissible for dataanalysis. The following parameters were estimated for each subject andtreatment, using the baseline-corrected plasma levels:

-   -   C_(max) (ng/ml)—largest observed plasma morphine value    -   T_(max) (hours)—time of occurrence of C_(max), relative to time        of dosing    -   T_(1/2) (elim; hours)—apparent half-life of plasma morphine        elimination calculated according to:        -   T_(1/2) (elim)—0.693/K_(e)    -   where K_(e) is the terminal first-order apparent elimination        rate constant calculated by PROC NLIN in SAS    -   Release 6.07 (SAS Institute, Cary, N.C.).    -   T_(1/2) (abs; hrs)—apparent half-life of absorption calculated        according to:        -   T_(1/2) (abs)—0.693/K_(a)

FIG. 9 is a graphical representation of the mean plasma morphineconcentration-time profile obtained with the Comparative Example (MSContin 30 mg) (fasted) as compared to the capsules of Example 1 (fed andfasted) and Example 2 (fasted).

From the results set forth above, it can be seen that the formulation ofExample 1 attains a higher and earlier Cmax but a slightly lower extentof morphine absorption than the formulation of Example 2. Visualexamination of the time-action data in respect to sedation, respiratoryrate, pupil size, and combined scores from a questionnaire of opioideffects reported by the subjects at serial times following eachtreatment reveals greater degree of intensity of each pharmacodynamicendpoint during the earlier (e.g., 4-8 hours) portion of the time-actioncurves.

EXAMPLE 3

Beads with a higher loading of morphine sulfate were produced with theuse of the powder layering technique in the Glatt Rotor Processor. Theformulation of the high load beads is set forth in Table 8 below: TABLE8 High Load Bead Percent Ingredient mg/unit (%) Morphine Sulfate Powder30.0 mg 63.3% Lactose 6.0 mg 12.7% Povidone C-30 1.25 mg 2.6% SugarBeads 7.75 mg 16.4% Opadry 2.37 mg 5.0% Purified Water qs — Total 47.37mg 100.0%

The sustained-release coating comprised an acrylic polymer (i.e.,Eudragit® RL). A HPMC protective coat was also included between theEudragit layer and the morphine immediate release layer to furtherenhance stability. The formula of the sustained release coating ofExample 1 is set forth in Table 9 below: TABLE 9 Amt/Unit PercentIngredient (mg) (%) Morphine (high load) base beads 42.63 mg  78.8% Retardant Coating Eudragit RS 30D  2.1 mg 3.9% Eudragit RL 30D 0.05 mg0.1% Triethyl Citrate 0.45 mg 0.8% Talc 0.85 mg 1.6% Overcoatings OpadryBlue YS-1-10542A 2.45 mg 4.5% Purified Water qs — Morphine SulfatePowder  3.0 mg 5.5% Opadry Blue YS-1-10542A 2.55 mg 4.8% Purified Waterqs — Total 54.08 mg  100.0% 

The sustained release and the immediate release coatings were applied asfollows. The Eudragit RL 30D was plasticized with triethyl citrate andtalc for approximately 30 minutes. A load of the morphine sulfate beadswas charged into a Wurster Insert of a Glatt equipped with a 1.2 mmspray nozzle and the beads are coated to a weight gain of 5%. The finalprotective Opadry dispersion overcoat was then applied in the WursterInsert. Upon completion the beads were cured for two days in a dry ovenof 45° C. The cured beads were then filled into gelatin capsules at a 30mg strength. The cured beads were then filled into gelatin capsules at astrength of 30 mg.

The capsules were then subjected to dissolution testing. Dissolutiontesting was conducted on the finished products via USP ApparatusII-(Paddle Method). The capsules were placed into 700 ml of simulatedgastric fluid (without enzymes) for the first hour at 100 rpm and 37°C., and then placed into 900 ml of simulated gastric fluid (withoutenzymes) after the first hour. The results of dissolution testing is setforth in Table 10 below: TABLE 10 Percent Morphine Time SulfateDissolved  1 hour 11.7%  2 hours 12.1%  4 hours 22.0%  8 hours 45.3% 12hours 63.7% 18 hours 81.8% 24 hours 92.5%Clinical Evaluation of Example 3

Thirteen normal, healthy male subjects were enrolled in this five-waycrossover, randomized, open-label study assessing the effect of food onthe pharmacokcinetics and pharmacodynamics of single 30-mg doses(capsules) of Example 3. The pharmacokinetic and pharmacodynamic resultsof the extended-release formulations in these fed and fasted subjectswere also compared with those of MS Contin® 30 mg tablets in fastedsubjects. Plasma morphine level was used to calculate pharmacokineticparameters including: (a) apparent absorption and elimination rates; (b)area-under-the-curve (AUC); (c) maximum plasma concentration (C_(max));(d) time to maximum plasma concentration (T_(max)); (e) T_(1/2) (abs),and (f) T_(1/2) (elim). Pharmacodynamic effects were assessed based onevaluations of mood, sedation, respiratory rate, pupillometry, andsubject's adjective questionnaire.

Plasma morphine concentrations were determined by a high-performanceliquid chromatographic procedure. All subjects completed the study andwere included in the biopharmaceutical analysis. Arithmetic meanC_(max), T_(max), AUC, half-lives calculated from individual plasmamorphine concentration-versus-time, and oral bioavailability data areset forth in Tables 11 and 12 below: TABLE 11 Pharmacokinetic Ex. 3 Ex.3 MS Contin ® Parameter (Fed) (Fast) (Fasted) C_(max) (ng/ml) 5.45 4.0311.65 T_(max) (hours) 8.04 12.92 2.77 AUC (0.72) (hr-ng/ml) 118.12140.79 114.05 AUC (0,00) (hr-ng/ml) 137.67 166.19 114.05 T _(1/2) (elim;hrs) 21.19 54.51 1.26 T _(1/2) (abs; hrs) 3.12 2.44 3.34

TABLET 12 Pharmaco- F_(o) (%) Ex. 3 vs. kinetic 90% C.I. MS Contin ®Parameter (Ex 3: Fed vs. Fast) (Both Fasted) C_(max) 164.36  29.54(ng/ml) (113.1-215.6) (14.3-44.7) T_(max)  53.49 514.28 (hours)(13.3-93.7) (306.8-721.7) AUC (0.72) 89.93 119.35 (hr-ng/ml)( 64.8-115.1) ( 89.2-149.5) AUC (0,00)  86.56 143.48 (hr-ng/ml)( 62.5-110.6) (108.6-178.1) T_(½)(elim; hrs) 34.53 1609.0 ( 7.4-61.7)(1170-2048) T_(½)(abs; hrs) 135.27 191.45 ( 83.5-187.0) ( 92.0-290.9)F_(o) (%) =Oral bioavailability (Test mean/Reference mean)

Table 13 provides the mean (±S.D.) plasma morphine concentrations(ng/ml) following dosing with MS Contin® and Example 3. TABLE 13 MeanPlasma Morphine Concentrations ± Standard Deviation FollowingAdministration Time Ex. 3 Ex. 3 MS Contin ® (hours) 30 mg Fed 30 mgFasted 30 mg Fasted 0.00 0.00 ± 0.00 0.00 ± 0.00 0.00 ± 0.00 0.50 0.201± 0.447 2.00 ± 1.48 3.42 ± 1.82 1.00 0.331 ± 0.479  2.27 ± 0.799 6.09 ±2.03 2.00 1.65 ± 1.53  2.19 ± 0.936 8.82 ± 2.61 2.50 3.06 ± 1.04  2.20 ±0.798 9.12 ± 2.97 3.00 3.53 ± 1.82 2.24 ± 1.05 9.91 ± 5.32 3.50 3.06 ±1.16 2.87 ± 1.94 8.83 ± 3.58 4.00 3.23 ± 1.04 2.33 ± 1.13 8.12 ± 3.265.00 4.01 ± 1.50  2.91 ± 0.933 7.79 ± 3.47 6.00 4.00 ± 2.09 2.96 ± 1.246.07 ± 3.69 8.00 4.03 ± 1.90 2.58 ± 1.24 4.68 ± 3.88 10.0 3.95 ± 1.89 1.95 ± 0.965 2.61 ± 1.43 12.0 3.20 ± 1.47  2.18 ± 0.983  1.58 ± 0.81518.0 2.06 ± 1.02 2.75 ± 1.53  1.46 ± 0.745 24.0  2.10 ± 0.963  2.72 ±0.971  1.34 ± 0.890 36.0 1.66 ± 1.05 2.65 ± 1.18  1.08 ± 0.971 48.00.872 ± 0.681  1.53 ± 0.851 0.528 ± 0.831 72.0 0.300 ± 0.529 0.468 ±0.650 0.00 ± 0.00

Table 14 provides the mean (±S.D.) pharmacokinetic parameters followingdosing with MS Contin® And Example 3. TABLE 14 Mean PharmacokineticParameters ± Standard Deviation Following Administration of EachFormulation Ex. 3 Ex. 3 Ms Contin ® Parameter 30 mg Fed 30 mg Fasted 30mg Fasted C_(max) 5.45 ± 1.68 4.03 ± 1.55 11.65 ± 4.82 (ng/ml) Tmax 8.04± 8.31 12.92 ± 14.66  2.77 ± 0.927 (hrs) AUC(0.72) 118.12 ± 36.77 140.79 ± 51.23  114.05 ± 42.42 (hr-ng/ml)

The ratios of least-squares mean AUC for the 30 mg capsules of Example 3given under fed and fasted conditions indicate that AUC values under fedconditions are within ±20% of those under fasted conditions. The valueof C_(max) was 64% greater under fed conditions. The value of T_(max)under fed conditions was approximately 50% of that when given underfasted conditions. The apparent absorption rate was approximately 35%greater under fed conditions, and the apparent elimination rate underfed conditions was approximately 35% of that under fasted conditions,indicating that absorption of morphine is slowed by the presence offood, and elimination rate is increased.

The ratios of least-squares mean AUC for the 30 mg capsule of Example 3and the MS Contin® 30 mg tablet indicate that AUC (0,72) values forExample 3 are within ±20% of those for MS Contin®, and AUC (0,00) valuesare 44% greater for Example 3. The value of C_(max) for Example 3 was29.5% of that for MS Contin®. The value of T_(max) under fed conditionswas over five times that for Example 3. The apparent absorption rate wasapproximately 91% greater for Example 3, and the apparent eliminationrate for Example 3 was over 16 times that for MS Contin®, indicatingthat absorption and elimination of morphine is slower for Example 3.

Linear regression of each pharmacodynamic parameter on thelog-transformed concentrations for each subject and treatment resultedin 74 of 315 regressions (24%) having an R² value of 20% or higher, and12 of 315 (4%) having a value of 50% or higher. When analyzed bytreatment only, there were zero R² values higher than 10%. Of thoseindividual R² values above 20%, 21 occurred in the 63 regressions (33%)of Subject's Modified Specific Drug Effect Questionnaire scores on logconcentration, and 7 of the 63 (11%) were above 50%. These valuesindicate a possible linear relationship between the log concentrationsand Subject's MSDEQ scores. Examination of the mean hysteresis curvesalso reveals a possible relationship between morphine concentration andSubject's MSDEQ scores. For each formulation, Subject Modified SpecificDrug Effect Questionnaire scores tended to increase with an increase inmorphine concentration, then decrease as morphine concentrationdecreased. No relationships were observed between morphineconcentrations and any of the other pharmacodynamic parameters.

FIG. 10 is a graphical representation of the mean plasma morphineconcentration-time profile obtained with the Comparative Example (MSContin 30 mg) (fasted) as compared to the capsules of Example 3 (fed andfasted). FIG. 11 is a graphical representation of the mean sedation vs.time curve for Example 3 (fasted). FIG. 12 is a graphical representationof the mean respiratory rate vs. time curve for Example 3 (fasted). FIG.13 is a graphical representation of the mean pupil size v. time curvefor Example 3 (fasted). FIG. 14 is a graphical representation of themean subject modified specific drug effect questionnaire vs. time curvefor Example 2 (fasted).

EXAMPLE 4

Beads with a higher loading of morphine sulfate were produced with theuse of the powder layering technique in the Glatt Rotor Processor. Theformulation of the high load beads is set forth in Table 15 below. TABLE15 High Load Percent Ingredient Bead mg/unit (%) Morphine Sulfate Powder60.0 mg 56.4% Lactose 12.0 mg 11.3% Eudragit RS30D 4.16 mg  3.9%Povidone C-30 8.31 mg  7.8% Sugar Beads 16.80 mg  15.8% Opadry 5.06 mg 4.8% Purified Water qs — Total 106.33 mg   100%

These immediate release base beads were manufactured using the powderlayering technique in the Glatt Rotor Processor.

The sustained release coating comprised an ethylcellulose acrylicpolymer (i.e., Aquacoat ECD 30). A HPMC protective coat was alsoincluded after the Aquacoat layer to further enhance stability. Theformula of the sustained-release coating of Example 1 is set forth inTable 16 below. TABLE 16 Ingredient Amt/Unit (mg) Percent (%) Morphine(high load) 106.33 mg  73.1% based beads Retardant Coating Aquacoat ECD30 23.13 mg  15.9% Methocel E5 Premium 3.46 mg 2.4% Triethyl Citrate5.32 mg 3.6% Purified Water qs — Final Overcoat Opadry Blue YS-1-10542A7.28 mg 5.0% Purified Water qs — Total 54.08 mg  100.0%

The sustained release coating and final overcoat were applied asfollows: The combination of Aquacoat ECD 30 and Methocel E5 Premium wasplasticized with triethyl citrate for approximately 30 minutes. A loadof morphine sulfate beads was charged into a Wurster Insert of a Glattequipped with a 1.2 mm spray nozzle and the beads are coated to a weightgain of 25%. Upon completion of the Retardant the beads were cured for 3days in a Temperature/Humidity Chamber of 60° C./80% RH. The cured beadswere then Lried for 1 day in a dry oven of 60° C. The cured dried beadswere charged into a Wurster Insert of a Glatt equipped with a 1.2 mmspray nozzle and the final protective Opadry dispersion overcoat wasthen applied. The finished sustained release beads along with the LowLoad Immediate Release Morphine Sulfate beads were individually filledinto the same gelatin capsules at a combined strength of 60 mg. Thesustained released beads comprised 90% or 54 mg of strength and theImmediate Release Beads comprised 10% or 6 mg of the capsule strength.

The capsules were then subjected to dissolution testing. Dissolutiontesting was conducted on the finished products via USP ApparatusII-(Paddle Method). The capsules were placed into 700 ml of simulatedgastric fluid (without enzymes) for the first hour at 100 rpm and 37°C., and then placed into 900 ml of simulated intestinal fluid (withoutenzymes) after the first hour. The results of dissolution testing is setforth in Table 17 below. TABLE 17 Time % Morphine Sulfate Dissolved 1hour  10.4% 2 hours 11.4% 4 hours 17.5% 8 hours 31.8% 12 hours  54.0% 18hours  88.6% 24 hours  102.3%

EXAMPLE 5

Beads with a higher loading of morphine sulfate were produced with theuse of the powder layering technique in the Glatt Rotor Processor. Theformulation of the high load beads is set forth as per Table 18 inExample 5.

The sustained-release coating comprised an acrylic polymer (i.e.,Eudragit® RS/RL). A HPMC protective coating was also included after theEudragit layer to further enhance stability. The formula of thesustained-release coating of Example 5 is set forth in Table 18 below.TABLE 18 Ingredient Amt/Unit (mg) Percent (%) Morphine (high load)106.33 mg  87.96%  based beads Retardant Coating Eudragit RS 30 D 5.05mg 4.18% Eudragit RL 30 D 0.27 mg 0.22% Triethyl Citrate 1.06 mg 0.88%Talc 2.13 mg 1.76% Final Overcoat Opadry Blue YS-1-10542A 6.04 mg  5.0%Purified Water qs — Total 120.88 mg  100.0% 

The sustained-release and the final coatings were applied as follows.The Eudragit RS/RL 30D was plasticized with triethyl citrate and talcfor approximately 30 minutes. A load of the morphine sulfate beads wascharged into a Wurster Insert of a Glatt equipped with a 1.2 mm spraynozzle and the beads are coated to a weight gain of 5%. The finalprotective Opadry dispersion overcoat was then applied in the WursterInsert. Upon completion the beads were cured for two days in a dry ovenof 45° C. The cured beads were then filled into gelatin capsules at a 60my strength.

The capsules were then subjected to dissolution testing. Dissolutiontesting was conducted on the finished products via USP Apparatus II(Paddle Method). The capsules were placed into 700 ml of simulatedgastric fluid (without enzymes) for the first hour at 100 rpm and 37°C., and then placed into 900 ml of simulated intestinal fluid (withoutenzymes) after the first hour. The results of dissolution testing is setforth in Table 19 below. TABLE 19 Time % Morphine Sulfate Dissolved 1hour  10.4% 2 hours 11.4% 4 hours 17.5% 8 hours 31.8% 12 hours  54.0% 18hours  88.6% 24 hours  102.3%

EXAMPLE 6 Matrix Beads

Matrix Beads with a higher loading of morphine sulfate were producedwith the use of the powder layering technique in the Glatt RotorProcessor. The formulation of the high load matrix beads is set forth inTable 20 below. TABLE 20 High Load Percent Ingredient Bead mg/unit (%)Morphine Sulfate Powder 60.0 mg 46.0% Lactose 12.0 mg  9.2% EudragitRS30D 29.10 mg 22.4% Povidone C-30 5.80 mg  4.5% Sugar Beads 16.80 mg 12.9% Opadry 6.50 mg  5.0% Purified Water qs — Total 130.20 mg   100%

The matrix component is comprised of an ethylcellulose polymer (i.e.,Aquacoat ECD 30). A HPMC protective coat was also included after theaquacoat layer to further enhance stability.

The matrix beads were made as follows. The Aquacoat ECD 30 wasplasticized with tributyl citrate for approximately 30 minutes. Morphinesulfate powder and lactose were blended for approximately 5 minutes in ahobart mixer. A load of sugar beads was charged into the rotor insert ofa Glatt equipped with a 1.2 mm spray nozzle/powder feed assembly. AnAccurate Powder Feeder was positioned over the spray nozzle/powder feedassembly and charged with the morphine sulfate/lactose blend. Themorphine sulfate/lactose blend is then layered onto the sugar beadsusing the plasticized hydrophobic polymer dispersion (i.e., Aquacoat ECD30 and tributyl citrate) as the binding agent. Upon completion of thelayering process the final protective Opadry dispersion overcoat wasthen applied. The beads were then cured for one day in a dry oven of 60°C. The cured beads were then filled into gelatin capsules at a 60 mgstrength.

The capsules were then subjected to dissolution testing. Dissolutiontesting was conducted on the finished products via USP ApparatusII-(Paddle Method). The capsules were placed into 700 ml of simulatedgastric fluid (without enzymes) for the first hour at 100 rpm and 37°C., and then placed into 900 ml of simulated intestinal fluid (withoutenzymes) after the first hour. The results of dissolution testing is setforth in Table 21 below. TABLE 21 Time % Morphine Sulfate Dissolved 1hour  32.4% 2 hours 44.8% 4 hours 59.6% 8 hours 76.6% 12 hours  88.0% 18hours  97.6% 24 hours  102.2%

CLINICAL EVALUATION OF EXAMPLES 4, 5 AND 6

Fourteen normal healthy human subjects were enrolled in a six waycrossover, randomized, open label study assessing the effect of food onthe pharmacokinetics and pharmacodynamics of a single dose of eitherexample 1, 2 or 3, with or without food. Plasma samples were analyzedfor morphine levels and the following pharmacokinetic results werecalculated, and the results are set forth in Table 22 below. TABLE 22Pharmacokinetic Parameter Per 60 mg Dose Example AUC Cmax Tmax Number(ng/ml · hr) (ng/ml) (hours) 1 Fasted 120 6.1 5.5 1 Fed 131 8.3 8.8 2Fasted 149 11.3 6.7 2 Fed 159 11.5 6.4 3 Fasted 154 14.3 1.8 3 Fed 15412.7 2.8

EXAMPLE 7 Hydromorplione HCl 8 mg Once-a-Day Capsules Drug Loading

Hydromorphone beads were prepared by dissolving hydromorphone HCl inwater, adding Opadry Y-5-1442 and mixing for about 1 hour to obtain a20% w/w suspension. This suspension was then sprayed onto Nu-Pareil18/20 mesh beads using a Wurster insert.

First Overcoat

The loaded hydromorphone beads were then overcoated with a 5% w/w gainof Opadry Light Pink using a Wurster insert. This overcoat was appliedas a protective coating.

Retardant Coat

After the first overcoat, the hydromorphone beads were then coated witha 5% weight gain of a retardant coating mixture of Eudragit RS 30D andEudragit RL 30D at a ratio of 90:10, RS to RL. The addition of TriethylCitrate (a plasticizer) and Talc (anti-tacking agent) was also includedin the Eudragit suspension. The Wurster insert was used to apply thecoating suspension.

Second Overcoat

Once the retardant coating was complete, the hydromorphone beads weregiven a final overcoat of Opadry Light Pink to a 5% weight gain using aWurster insert. This overcoat was also applied as a protective coating.

Curing

After the completion of the final overcoat, the hydromorphone beads werecured in a 45° C. oven for 2 days.

Encapsulation

Beads were hand filled in size #2 clear gelatin capsules at an 8 mgstrength of Hydromorphone HCl.

The formulation for Example 7 is set forth in Table 23 below: TABLE 23HYDROMORPHONE HCl 8 mg ONCE A DAY CAPSULES Ingredient mg/Capsule LoadingHydromorphone HCl 8.00 Opadry Light Pink (Y-5-1442) 4.00 Purified Water¹q.s. 18/20 Mesh Sugar Spheres 148.00 Overcoating Opadry Light Pink(Y-5-1442) 8.40 Purified Water¹ q.s. Retardant Coating Eudragit RS 30D²7.60 Eudragit RL 30D² 0.80 Triethyl Citrate 1.68 Talc 3.36 PurifiedWater¹ q.s. Second Overcoating Opadry Light Pink (Y-5-1442) 9.60Purified Water¹ q.s. Encapsulation Size #2 Clear Hard Gelatin Capsulesn/a Total Fill Weight 191.44 mg¹Used in processing and remains as residual moisture only.²Dry weight.Dissolution Testing

The above capsules were tested using USP methodology and were found tohave the following results: Time Initial 1 hour 17.2 2 hours 48.4 4hours 77.4 8 hours 93.3 12 hours 97.2 18 hours 98.8 24 hours 98.8

A single-dose randomized, crossover bioavailability study was conductedwith the above 8 mg controlled release hydromorphone HCl capsules andtwo immediate release 4 mg tablets (Dilaudid®) as the reference in fedand fasted conditions. Blood samples were assayed for hydromorphonelevels and the following pharmacokinetic parameters were calculated. Theresults are provided in Table 24 below: TABLE 24 AUC T_(max) C_(max)T_(1/2) Group (pg/ml/hr) % IR (hr) (pg/ml) (abs) CR Fasted* 21059 1014.9 1259 2.56 CR Fed* 25833 106 4.6 1721 3.92 IR Fasted** 20903 100 0.853816 0.18 IR Fed** 24460 100 1.15 3766 0.32*CR = Example 7**IR = Dilaudid

The examples provided above are not meant to be exclusive. Many othervariations of the present invention would be obvious to those skilled inthe art, and are contemplated to be within the scope of the appendedclaims.

1. An oral sustained release opioid formulation comprising: (a) aneffective amount of an opioid analgesic, and (b) an effective amount ofat least one retardant material to cause said opioid analgesic to bereleased at an effective rate to provide an analgesic effect after oraladministration to a human patient for at least about 12 hours. 2-4.(canceled)
 5. The sustained release formulation of claim 1, wherein saidopioid analgesic is selected from the group consisting of alfentanil,allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide,buprenorphine, butorphanol, clonitazene, codeine, cyclazocine,desomorphine, dextromoramide, dezocine, diampromide, dihydrocodeine,dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene,dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine,ethylmethylthiambutene, ethylmorphine, etonitazene fentanyl, heroin,hydrocodone, hydromorphone, hydroxypethidine, isomethadone,ketobemidone, levallorphan, levorphanol, levophenacyl morphan,lofentanil, meperidine, meptazinol, metazocine, methadone, metopon,morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol,normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone,oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan,phenazocine, phenoperidine, piminodine, piritramide, propheptazine,promedol, properidine, propiram, propoxyphene, sufentanil, tramadol,tilidine, salts thereof and mixtures thereof. 6-26. (canceled)
 27. Thesustained release formulation of claim 1, wherein said opioid analgesicis oxymorphone.
 28. The sustained release formulation of claim 1,wherein the retardant material comprises a sustained release coating ora sustained release matrix.
 29. The sustained release formulation ofclaim 1, wherein said formulation provides a maximum blood plasmaconcentration of the opioid analgesic, or of a metabolite thereof, afteroral administration to the human patient, which maximum blood plasmaconcentration: (i) provides a susbstantially equivalent therapeuticeffect as 2-14 ng/ml morphine based on a 30 mg dose of morphine sulfate;and (ii) is less than about four times a blood plasma concentration ofthe opioid analgesic, or of a metabolite thereof, at about 12 hoursafter administration.
 30. The sustained release formulation of claim 29,wherein the opioid analgsic is oxymorphone.
 31. The sustained releaseformulation of claim 29, wherein the maximum blood plasma concentrationprovides a substantially equivalent therapeutic effect as 3-8 ng/mlbased on a 30 mg dose of morphine sulfate.
 32. The sustained releaseformulation of claim 29, wherein the blood concentration of the opioidanalgesic, or of a metabolite thereof, at about 12 hours after oraladministration to the human patient is at least a minimally effectiveanalgesic concentration.
 33. The sustained release formulation of claim1, wherein said formulation provides a blood plasma concentration of theopioid analgesic, or of a metabolite thereof, at about 12 hours afteroral administration to the human patient, which blood plasmaconcentration: (i) is at least a minimally effective analgesicconcentration for the opioid analgesic; and (ii) is at least about 25%of a maximum blood concentration of the opioid analgesic, or of ametabolite thereof, after oral administration to the human patient. 34.The sustained release formulation of claim 33, wherein the opioidanalgesic is oxymorphone.
 35. The sustained release formulation of claim33, wherein the blood plasma concentration is provided after oraladministration of a single dose to the human patient.
 36. The sustainedrelease formulation of claim 33, wherein the blood plasma concentrationis provided upon repeated oral administration of said formulation to thehuman patient through steady state conditions.
 37. The sustained releaseformulation of claim 33, wherein the maximum blood plasma concentrationprovides a substantially equivalent therapeutic effect as 2-14 ng/mlmorphine based on a 30 mg dose of morphine sulfate.
 38. The sustainedrelease formulation of claim 35, wherein the maximum blood concentrationprovides a substantially equivalent therapeutic effect as 3-8 ng/mlmorphine based on a 30 mg dose of morphine sulfate.
 39. A method oftreating a patient for pain, which method comprises orally administeringto the patient a formulation which comprises an effective amount of anopioid analgesic, wherein said formulation provides analgesia to apatient for at least about 12 hours after administration.
 40. The methodof claim 39, wherein said opioid analgesic is selected from the groupconsisting of alfentanil, allylprodine, alphaprodine, anileridine,benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene,codeine, cyclazocine, desomorphine, dextromoramide, dezocine,diampromide, dihydrocodeine, dihydromorphine, dimenoxadol,dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone,eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine,etonitazene fentanyl, heroin, hydrocodone, hydromorphone,hydroxypethidine, isomethadone, ketobemidone, levallorphan, levorphanol,levophenacyl morphan, lofentanil, meperidine, meptazinol, metazocine,methadone, metopon, morphine, myrophine, nalbuphine, narceine,nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine,norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine,phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine,piritramide, propheptazine, promedol, properidine, propiram,propoxyphene, sufentanil, tram adol, tilidine, salts thereof andmixtures thereof.
 41. The method of claim 39, wherein said opioidanalgesic is oxymorphone.
 42. The method of claim 39, wherein said oraladministration provides a maximum blood concentration of the opioidanalgesic, or of a metabolite thereof, which maximum blood plasmaconcentration: (i) provides a substantially equivalent effect as 2-14ng/ml morphine based on a 30 mg dose of morphine sulfate; and (ii) isless than about four times a blood plasma concentration of the opioidanalgesic, or of a metabolite thereof, at about 12 hours afteradministration.
 43. The method of claim 42 wherein the opioid analgesicis oxymorphone.
 44. The method of claim 39, which formulation provides ablood plasma concentration of the opioid analgesic, or of a metabolitethereof, at about 12 hours after said administration, which blood plasmaconcentration is at least a minimally effective analgesic concentrationfor the opioid analgesic; and wherein a maximum blood concentration ofthe opioid analgesic, or of a metabolite thereof, is less than aboutfour times said blood plasma concentration at about 12 hours after oraladministration to the human patient.
 45. The method of claim 44 whereinthe opioid analgesic is oxymorphone.